{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T07:47:52Z","timestamp":1781768872677,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374061"],"award-info":[{"award-number":["82374061"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2024-I2M-ZH-012, 2022-I2M-1-016"],"award-info":[{"award-number":["2024-I2M-ZH-012, 2022-I2M-1-016"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"],"award-info":[{"award-number":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["82374061"],"award-info":[{"award-number":["82374061"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2024-I2M-ZH-012, 2022-I2M-1-016"],"award-info":[{"award-number":["2024-I2M-ZH-012, 2022-I2M-1-016"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"],"award-info":[{"award-number":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"]}]},{"name":"Key Project Fund of the Chinese Academy of Engineering","award":["82374061"],"award-info":[{"award-number":["82374061"]}]},{"name":"Key Project Fund of the Chinese Academy of Engineering","award":["2024-I2M-ZH-012, 2022-I2M-1-016"],"award-info":[{"award-number":["2024-I2M-ZH-012, 2022-I2M-1-016"]}]},{"name":"Key Project Fund of the Chinese Academy of Engineering","award":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"],"award-info":[{"award-number":["Organized Scientific Research Strategy Study on Anti-Infective Drugs for Emerging Infectious Diseases, 2025-XZ-125"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background and purpose: Vulvovaginal candidiasis (VVC), caused by Candida albicans (C. albicans), is exacerbated by oxidative stress and uncontrolled inflammation. Pathogens like C. albicans generate reactive oxygen species (ROS) to enhance virulence, while host immune responses further amplify oxidative damage. This study investigates the antioxidant and antifungal properties of Hyssopus cuspidatus Boriss volatile extract (SXC), a traditional Uyghur medicinal herb, against fluconazole-resistant VVC. We hypothesize that SXC\u2019s bioactive volatiles counteract pathogen-induced oxidative stress while inhibiting fungal growth and inflammation. Methods: GC-MS identified SXC\u2019s major bioactive components, while broth microdilution assays determined minimum inhibitory concentrations (MICs) against bacterial\/fungal pathogens, and synergistic interactions with amphotericin B (AmB) or fluconazole (FLC) were assessed via time\u2013kill kinetics. Anti-biofilm activity was quantified using crystal violet\/XTT assays, and in vitro studies evaluated SXC\u2019s effects on C. albicans-induced cytotoxicity (LDH release in A431 cells) and inflammatory responses (cytokine production in LPS-stimulated RAW264.7 macrophages). A murine VVC model, employing estrogen-mediated pathogenesis and intravaginal C. albicans challenge, confirmed SXC\u2019s in vivo effects. Immune modulation was assessed using ELISA and RT-qPCR targeting inflammatory and antioxidative stress mediators, while UPLC-MS was employed to profile metabolic perturbations in C. albicans. Results: Gas chromatography-mass spectrometry identified 10 key volatile components contributing to SXC\u2019s activity. SXC exhibited broad-spectrum antimicrobial activity with MIC values ranging from 0.125\u201316 \u03bcL\/mL against bacterial and fungal pathogens, including fluconazole-resistant Candida strains. Time\u2013kill assays revealed that combinations of AmB-SXC and FLC-SXC achieved sustained synergistic bactericidal activity across all tested strains. Mechanistic studies revealed SXC\u2019s dual antifungal actions: inhibition of C. albicans hyphal development and biofilm formation through downregulation of the Ras1-cAMP-Efg1 signaling pathway, and attenuation of riboflavin-mediated energy metabolism crucial for fungal proliferation. In the VVC model, SXC reduced vaginal fungal burden, alleviated clinical symptoms, and preserved vaginal epithelial integrity. Mechanistically, SXC modulated host immune responses by suppressing oxidative stress and pyroptosis through TLR4\/NF-\u03baB\/NLRP3 pathway inhibition, evidenced by reduced caspase-1 activation and decreased pro-inflammatory cytokines (IL-1\u03b2, IL-6, TNF-\u03b1). Conclusions: SXC shows promise as a broad-spectrum natural antimicrobial against fungal pathogens. It inhibited C. albicans hyphal growth, adhesion, biofilm formation, and invasion in vitro, while reducing oxidative and preserving vaginal mucosal integrity in vivo. By disrupting fungal metabolic pathways and modulating host immune responses, SXC offers a novel approach to treating recurrent, drug-resistant VVC.<\/jats:p>","DOI":"10.3390\/antiox14091046","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:25:57Z","timestamp":1756189557000},"page":"1046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hyssopus cuspidatus Boriss Volatile Extract (SXC): A Dual-Action Antioxidant and Antifungal Agent Targeting Candida albicans Pathogenicity and Vulvovaginal Candidiasis via Host Oxidative Stress Modulation and Fungal Metabolic Reprogramming"],"prefix":"10.3390","volume":"14","author":[{"given":"Yun-Dan","family":"Guo","sequence":"first","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan-Yong","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0073-4357","authenticated-orcid":false,"given":"Yan-Xing","family":"Han","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Le","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Tie","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Fine Exploration and Intelligent Development of Coal Resources & School of Chemical and Environmental Engineering, China University of Mining and Technology (Beijing), Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Dong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/QCO.0000000000000903","article-title":"Prevention and treatment of recurrent cellulitis","volume":"36","author":"Peghin","year":"2023","journal-title":"Curr. 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